A Genome Scan for Type 2 Diabetes Susceptibility Loci in a Genetically Isolated Population
- Marshall A. Permutt1,
- Jonathon C. Wasson1,
- Brian K. Suarez2,
- Jennifer Lin2,
- Jeffrey Thomas3,
- Joanne Meyer4,
- Steve Lewitzky4,
- Jean S. Rennich4,
- Alex Parker4,
- Laura DuPrat4,
- Sanchit Maruti4,
- Susan Chayen5 and
- Benjamin Glaser5
- 1Division of Metabolism, Endocrinology, and Diabetes and the
- 2Department of Psychiatry, Washington University Medical School, St. Louis, Missouri
- 3Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan
- 4Millennium Pharmaceuticals, Cambridge, Massachusetts
- 5Department of Endocrinology and Metabolism, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
Abstract
A total of 896 individuals of Ashkenazi Jewish descent were ascertained in Israel from 267 multiplex families, including 472 sib-pairs affected with type 2 diabetes. A genome-wide scan with average marker spacing of 9.5 cM revealed five regions on four chromosomes (4q, 8q, 14q, and 20q) that exhibited nominal evidence for linkage (P < 0.05). The highest observed nonparametric linkage Z score was 2.41 (equivalent to a logarithm of odds score of 1.26) at marker D4S1501. A maximal signal, with a Z score of 2.05, was observed on chromosome 20 near marker D20S195, and another on 20p near marker D20S103 (Z 1.80). A single marker on chromosome 8 (D8S593) and two adjacent markers on chromosome 14 (D14S749 and D14S605) also attained evidence of linkage. To explore the hypothesis that the signals on chromosomes 4 and 20 are differentially attributable to variation in BMI or age of onset, an ordered subset analysis was conducted. This analysis revealed that only when the families were ranked by BMI (in increasing order) did a subset attain nominal significance, and only for chromosome 4. The findings reported here lend credence to the hypothesis, now supported by four studies of Caucasian populations and most recently by a combined analysis of 1,852 pedigrees, that a type 2 diabetes susceptibility locus resides on chromosome 20q. This population, because of its unique genetic attributes, may facilitate identification of this and other genes contributing to type 2 diabetes.
- ASP, affected sib-pair
- CEPH, Centre d’Etude du Polymorphisme Humain
- LOD, logarithm of odds
- NPL, nonparametric linkage
- OGTT, oral glucose tolerance test
Footnotes
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Address correspondence and reprint requests to M. Alan Permutt, MD, Metabolism Division, Washington University School of Medicine, 660 S. Euclid, Box 8127, St. Louis, MO 63110. E-mail: apermutt{at}imgate.wustl.edu.
Received for publication 29 October 2000 and accepted in revised form 22 November 2000.
Additional information can be found in an online appendix at www.diabetes.org/diabetes/appendix.asp.
J.T. holds stock in Parke-Davis Pharmaceutical Research.
